The long-term goals of this project are to identify the events responsible for optic neuropathy that develops in glaucoma, and to identify strategies that prevent or delay this vision loss. Activated astrocytes are considered to play an essential role in the development of glaucoma, serving as a cellular source for cytotoxic substances that participate in ganglion cell death, and enzymes responsible for extracellular matrix remodeling associated with optic nerve head cupping. Hence, understanding these events that contribute to astrocyte activation will provide new insights into the pathogenesis of glaucoma and open new strategies for treating this disease. Investigations into intracellular systems that regulate cell function have focused almost exclusively on protein phosphorylation. In recent years, a second parallel intracellular system involving protein acetylation also has been shown to play a major role in regulating cellular function. In this system, protein acetylation and deacetylation are catalyzed by histone acetyltransferases and by histone deacetylases (HDACs), respectively. Under physiological conditions, protein acetylation regulates gene expression, metabolism, development and aging, while dysregulation of acetylation has been linked to the pathogenesis of cancer, cardiovascular disease, rheumatoid arthritis and neural degeneration. Studies by this lab have shown that the administration of HDAC inhibitors protects the retina from injury and this response is associated with suppression of astrocyte activation. Preliminary results presented in this application, provide evidence that the administration of HDAC inhibitors to ocular hypertensive animals provides both structural and functional protection to the retina. Using in vivo and in vitro models, we have also shown that HDACs play a central role in modulating expression and secretion of TNF-1 from the optic nerve tissue, and block the cytokine-induced expression of matrix metalloproteinases (MMPs). Based upon these studies, we hypothesize that protein acetylation plays a central role in regulating astrocyte activation and the resulting neural degeneration in glaucomatous optic neuropathy. To investigate this hypothesis we propose three Specific Aims: 1) Investigate the potential of modulating protein acetylation as a strategy to protect retinal ganglion cells from ocular-hypertensive injury;2) Investigate the role of protein acetylation and individual HDAC isoforms in the expression and secretion of inflammatory cytokines from optic nerve astrocytes;and 3) Determine which HDAC isoforms mediate MMP expression and identify the cellular mechanisms by which HDACs regulate this expression in astrocytes. The results from these studies will: 1) improve our understanding of the role protein acetylation and HDACs play in regulating normal optic nerve astrocyte function, and how these processes can contribute to or limit astrocyte activation following injury;2) demonstrate how protein acetylation influences neuroinflammatory processes in the optic nerve and retina;and 3) provide a rational basis for the development of HDAC inhibitors as neuroprotective agents for the treatment of glaucoma and other optic neuropathies. PUBLIC HEALTH RELEVANCE: Glaucoma is one of the leading causes of blindness worldwide. Although a major risk factor for the development of glaucoma is elevated intraocular pressure, many individuals exhibit significant optic nerve damage and vision loss in the absence of any documented elevation in intraocular pressure, and as a result, many clinicians now recognize the need to develop new therapeutic strategies that directly target neuronal injury in these individuals. Based on our recent discoveries, we have developed the novel hypothesis that protein acetylation plays a central role in the neurodegeneration associated with glaucoma;if this hypothesis is proven correct, it will open completely new therapeutic strategies for treating this blinding disease.